Diastolic Cardiomyopathy Secondary to Experimentally Induced Exacerbated Emphysema

Chronic Obstructive Pulmonary Disease (COPD) is a clinical entity of increasing significance. COPD involves abnormalities of the airways and in emphysema, parenchymal pulmonary destruction. Cardiovascular Disease has emerged as a significant comorbidity to COPD. Heart Failure with preserved Ejection Fraction (HFpEF) appears to be particularly associated with COPD-Emphysema. Traditional treatments have shown limited efficacy in improving COPD associated HFpEF. This lack of therapeutic efficacy highlights the need to identify potential mechanisms that link COPD-Emphysema to HFpEF. Therefore, we aimed to study the delayed cardiac physiological impacts in a rat model with acute exacerbated emphysema. Emphysema was induced by 4 weekly 4UI Elastase and exacerbation by one final additional LPS intra-tracheal pulmonary instillations in male Wistar rats. At 5 weeks following the LPS/Elastase exposure, in-vivo and ex-vivo pulmonary and cardiac measurements were performed. Experimental exacerbated emphysema resulted in decreased pulmonary function and exercise intolerance. Histological analysis revealed parenchymal pulmonary destruction without signs of inflammation or cardiac fibrosis. In-vivo cardiac functional analysis revealed diastolic dysfunction and tachycardia. Ex-vivo analysis revealed a cellular cardiomyopathy with decreased myofilament Ca2+ sensitivity, cross-bridge cycling kinetics and increased adrenergic PKA-dependent phosphorylation of troponin-I. Experimental exacerbated emphysema was associated with exercise intolerance that appeared to be secondary increased β-adrenergic tone and subsequent cardiac myofilament dysfunction. A β1-receptor antagonist treatment (bisoprolol) started 24h post ELA-LPS instillation prevented in-vivo and ex-vivo diastolic dysfunction. These results suggest that novel treatment strategies targeted to the cardiac myofilament may be beneficial to combat exacerbated emphysema associated HFpEF.

COPD; HFpEF; calcium; cardiac myofilaments; elastase.